This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. alpha-Synuclein (alpha-syn) has been implicated in the pathogenesis of a number of neurodegenerative diseases, the best known of which is Parkinson?s disease (PD). The sporadic form of PD has been linked to environmental factors that promote oxidative stress and aberrant redox-active metal metabolism, and metal-enhanced oligomerization of alpha-syn has been observed in vitro. Recent work in our laboratory has focused on the understanding the role of copper ions in the aggregation of alpha-syn. Our initial studies have shown that Cu(II) ions accelerate aggregation and that the copper ions are incorporated into alpha-syn, with the tightest affinity binding near the N-terminus (based on ICP-MS and fluorescence quenching). We propose Cu K-edge and EXAFS studies to examine the local structure of the Cu binding site in the WT protein and in related mutants. We will compliment these studies with XAS on synthetic N-terminal fragments in order to identify the Cu binding site ligands. Our studies will examine both Cu(II) and Cu(I) binding to the protein, as these results could potentially provide insights into the role of redox chemistry in alpha-syn pathology. Once the soluble Cu-protein complexes have been characterized, we are poised to examine alpha-syn fibrils generated in the presence of copper ions.